Aug. 20, 1955
-/-3054”; c = 0.10; temp. 30.5-31”. Drude equation: [MI = 115/(X2 - 0.0868) - 55.7/X2; XO 294 mfi; yo deviation [Mlobsd - [M]onlod: &2.2%, 550-355 mp. Androstan-17-one (111), m.p. 119-120’; Amax. 294-297 mp, log E 1.83; supplied by Syntex, S. A . R. D . (Fig. 1): [ a 1 7 0 0 A- 44’, [ a ] m 82”, - 250”, “max.” [alszo 2572; c = 0.10; temp. 29-31 . Drude equation: [MI = 69.7/(X2 - 0.0942) - 17.3/Xz; Xo 307 mp; % deviation [ h f l o b s d - [M]ce~cd: =t1.7%, 589-340 mp f 2 . 7 % , 589-325 m w . Androstan-3-one (IV), m.p. 99.2-99.8’; A,,. 284-287 mp, log E 1.67; supplied by Dr. H. B . iMacPhillamy, Ciba Pharmaceutical Products, Inc. R.D. (Fig. 1): [a]700 17.0”, [ a ] s ~ 9 25.0”, [ a 1 3 0 0 212O, “max.” [ a ] ~ , 916”; c = 1.00 from 700-320 m p , c = 0.10 from 360-300 m p ; temp. 24’. Drude equation: [MI = 17.1/(Xz - 0.0987); Xo 314 mp; deviation [Mlabsd - [M]ea~od:*2.2%, 650-360 mp. Androstane ( V ) , m.p. 40-43”. R.D. (Fig. 1): O.to, [ o l ] 5 6 g 0.7”,[ a 1 3 3 0 11.8”; c = 1.00; temp. 2829 . Drude equation: [MI = 2.53/(X2 - 0.0550) 1.75/X2; XO 231 mp; ‘c deviation [Mjobsd - [MIcslcd 3 ~ 1 . 0(18.9 ~ - 0.3%), 520-330 mp, =t1.So (63.0-0.3%), 700-330 m p ; see comments in Discussion section concerning this deviation. A4-Androstene-3,17-dione(VI), m.p. 178-179’, Xmx. 304 mu. log e 1.79. shoulders 297. 313, 327-332 mu. log e 1.76, 1176r1.65; inflections 340; 346; 356, 360 m i , log e 1.56, 1.51, 1023, 1.13; from Syntex, S.A. R.D. (Fig. 2): [a1700 1‘:1 , [ ~ I B Q 176” [:I310 +26!?’, “max.”[al385 546 , min. [ a ] g 7 . 5 408 , “max. [ a ~ ; ~ ~55Z0, . ~ “ m i n . ” [ a ] 3 ~ 520 , “max.”[a]320 3650 ; c = 0.10; temp. 24-25’; R . D . : [a1700 122.7’, [ a ] 6 t i g +184.6”, [7]400+516.2 ; c = 1.00; temp. 24-25’. Drude equation: [XI = 151/(X2 - 0.0627), from c = 1.00 data; XO 250 mp; % deviation [ M ] ’ l l o ~ s d- [hflcalcd: fO.770, 700-425 mp.
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ROTATORY DISPERSION O F STEROID HORMONES
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A1,4-Androstadiene-3,17-dione (VII), m.p. 140-143”; 347-348, 336-337 mp, log E 1.36, 1.41; inflections 364, 357, 303, 293 mp, log e 1.16, 1.24, 1.75, 1.81; from Syntex, S.A. R.D. (Fig. 2): [ a 1 7 0 0 +78”, [?I5s9 +l;l;; [ a 1 3 0 5 +1294”, slight “ r n a x . ” [ ~ ~ ] ~345”, ~ ~ . ~slight “min. [~Y]365 337”, “ m a x . ” [ ~ ~ ] ~3087’; ~~ c = 0.10; temp. 68.2”, [0l]5s9 103.8’, 23.5-24.5’. R.D.: [a1700 [7]400+328.6”; c = 1.00; temp. 24-25’. Drude equation: [MI = 80.9/(Xz - 0.0784), from c = 1.00 data; Ail 280 m p ; % deviation [Mlobsd - [MIoalod: f 2 . 2 % , 700425 mp. AI-Androstened , 17-dione (VIII), m .p . 141-142 ’; A,,, 294-304 mp, log e 1.98, shoulder 332-340 mp, log E 1.70. R.D. (Fig. 2): [ C Y ] ~ O , O +83”, [ a 1 5 6 9 128”; [a)jos +1907’, “max.”[a141~. +286 , “ m i n . ” [ ~ ~ ] ~4-53 ~ ~ . ,6 m a ~ . ” [ a ] ~ ~ ~ 4- 296”, “min.”[a]~~7.t, f 288”, “rnax.”[cu]rn~ 3816”; c = 0.10; temp. 2526.5’. A4,6-Androstadiene-3,17-dione(IX), m.p. 168-169.5” ; X,, 336-346 mp, log e 1.87; inflection 362, 371, 377, 390 mu. log e 1.76. 1.63. 1.53. 1.13. R . D . IFig. 3): CY^,,,,, +7’3’, - 1 c y 1 ~ 9 +i3g0, ’[a]315 + ~ x o , ~ ~ m a x . ~ ~ [ a+1&.iS; ~pO~.~ “min. ” [ a ]403.5 1533”, “max. ” [a]390 1795”, “min. ” [ a 1 3 ( 0 -1030”; c = 0.10; temp. 24$?5’. R.D.: [a],O0 +73.8”, 1.1589 138.6., [ a 3 4 2 6 971.4 ; c = 1.00; temp. 24-25’. Drude equation: [MI = 70.1/(X2 . . - 0.167): XO 408 mu; % deviation [M]obsd’- [MIcslcd: &1.3%, 675525 mp; f3.3Y0 700-500 mp. A1,4,6-Androstatriene-3,17-dione(X), m.p. 165-168”; A,,=,. 346-348 mp, log E 1.98, shoulder 360 m p , log E 1.93; inflections 370, 377, 382,388 m p , log e 1.83, 1.77, 1.70, 1.54. R.D. (Fig. 3 ) : [ ~ I ~ o+32”, o [01]6ti9 +71”, [ c x I ~ ~ o- 137”, “ m a x . ” [ a 1 4 ~ ~ 2072”, “ m i n . ” [ ~ ~ ] 3 ~ ~1565O, [ ~ / ] ~ ~ i . ~ +1572O, “ m i n . ” [ o i ] ~- 1446’; c = 0.10; temp. 26-28”. R.D.: I a I i o o f 27.5’, [ ~ ] 6 s g 67.8”, [01]42j 959.2’; c = 1.00; temp. 24-25’. DETROIT,MICHIGAN A,.,
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DEPARTMEXT O F CHEMISTRY O F WAYNE USIVERSITY]
Optical Rotatory Dispersion Studies. 11.
Steroid H o r r n o n e ~ * ~ ~
BY ELEANOR W. FOLTZ, A. E. LIPPMAN AND CARLDJERASSI RECEIVEDMARCH16, 1955 The rotatory dispersion curves of testosterone, progesterone and of all the important estrogenic and cortical hormones are given, emphasis being placed on the correlation of certain structural features with the shapes of the dispersion curves.
The ultimate aim of this series of investigations is to provide an additional tool for the identification of certain structural features in the steroid series and the present paper is concerned with an examination of the rotatory dispersion curves of the most important, physiologically active, steroid hormones. The estrogenic hormones differ from all other naturally occurring steroids in possessing an aromatic ring A with consequent absence of the C-19 angular methyl group. The aromatic nature of ring A causes intense absorption near 280 mp4 but it was nevertheless possible in several instances to carry dispersion measurements to the neighborhood of 305 mp. Estradiol (IV) represents the basic compound in this series since the phenolic ring is the only important chromophore and its rotatory dispersion curve (1) Paper I, C. Djerassi, E. W. Foltz a n d A. E. Lippman, THIS 7 7 , 4354 (1956).
JOURNAL,
(2) Presented in part a t t h e December 1954 Meeting of t h e American Association f o r t h e Advancement of Science in Berkeley, California. (3) Supported by a research grant from t h e Damon Runyon hIemoria1 F u n d for Cancer Research (4) CY. L. Dorfman. Chein. Rers., 5 3 , 47 (1953).
ELEANOR Sr.FOLTZ, A.E. LIPPMAN AND CARLDJERASSI
4360
Vol. 77
(Fig. 1) shows a slow rise in a positive direction with although the first alternative may well be true as decreasing wave length. Estrone (11),on the other the introduction of an isolated 6,7-double bond hand, which possesses a 17-keto group shows the generally causes a large negative rotation a t the sotypical sharp rotation peak a t 320 mp assigned to dium D line6 and, in fact, over the entire spectral this group.’ Equilin (I), with an additional non- range studied.’ conjugated double bond, exhibits essentially the CIIBOH same type of curve, the highly positive 17-keto peak c-0 being located a t ca. 317.5 mp. Measurements on R II I equilenin (111) could not be carried further than 360 mp because of the intense light absorption up to 340 mp associated with the naphthol s y ~ t e m . ~ The shape of the curve (Fig. 1), however, does suggest that a rotation peak similar t o that in the other two carbonyl containing estrogens (I, 11) exists here also. CHiOH
i
CHzOH I
C=O ’ .OH
c-0
0
The remaining hormones to be discussed all possess the A4-3-keto grouping and their rotatory dispersion curves all show the “niaximumJJ8a t 357.5-360 mp and “minima” a t 36’7.5-370 mp and 852.5-355 m p which have been Shawn earlier‘ to be characteristic of A4-3-ketones. Neither the wave length a t which this feature appears nor the distance in terms of rotation between the positive (357.5-300 mp) and negative (367.5-370 n ~ p peaks ) I * I (‘Le., the degree of optical activity of the chromo-I I I I I I , 1 1 phore concerned) are altered with varying substi300 500 700 W A V E LENGTH (mp). tution a t C-11 or C-17. Inspection of Figs. 2 and 3 Fig. 1.-Rotatory dispersion curves of: equilin ( I ) , estrone demonstrates, however, that when the position of ( I I ) , equilenin (111),estradiol (IV), 6-dehydroestradiol (V). these peaks on the rotation scale is considered, the compounds fall into three groups: (a) the positive The rotatory dispersion curve (Fig. 1) of ii-dehy- (360 m p ) peak of testosterone (VII) occurs a t [ a ] droestradiol (V) is interesting when contrasted to - SSO,(b) that of progesterone (VI), corticosterone that of estradiol ( 1 1 7 ) . While the latter rises slowly (X), hydrocortisone (XI) and 1l-desoxycorticosterin a positive direction, the introduction of the 0 , i - one (XII) ranges between [ a ] +428O and +578O, double bond i n V causes the rotatioii to be negative while (c) that of the 1I-ketosteroids, 1l-dehydrothroughout the range measured, increasing in steep- corticosterone (VIII) and cortisone (IX) is found ness to the h r g e negative value of [ a ] -1602” a t in theregion [ a ]+10lljo to f1058’. Before proceeding to interpret this division into :3Y5 mp beyond which measurements could not be taken because of the strong light absorption a t 302 three groups on the basis of the in,tensity of the A4nip associated with this c h r ~ m o p h o r e . ~ IVhether 3-keto 350-400 mp region, it is necessary to conthis striking effect is due to the particular location (6) D. H. K. Barton and W. J. Rosenfelder, N a h ‘ e , 164,310 (1Qi9); of the double bond within the molecule or to the 0. Wintersteiner and M , l f o o r e , ibid., 164, 317 (1049), and later papers fact that it is in conjugation with the aromatic by both groups. ( 7 ) A . E. l,ipym.in, 1:. U’.F d t z and C. Iljerassi, ’ I H I Y J U L ’ X N A I . , 7 7 , ring -1 cannot be tlccided definitely a t this point, 43li4 (1953).
t I
1
I
( 3 ! C . Djerasil, G . Rosenkranz, J . liomu, S I’ataki. THISJouKsar., 7 2 , 4534 (1952).
Kaulni.rnn
and J .
(8) See reference 1 f o r definition of terms and experimental prucedure.
Aug. 20, 1955
ROTATORY DISPERSION OF STEROID HORMONES
-
2
350
436 1
400 450 WAVE LENGTH [An.).
Fig. 3.-Rotatory dispersion curves (330-470 mp) of: 11-dehydrocorticosterone (VIII), cortisone (IX), corticosterone (X), hydrocortisone (XI), 11-desoxycorticosterone (XII).
38
r.
0 34 x
z E! I-
Fig. 2.-Rotatory
dispersion curves of: progesterone (\'I), testosterone (VII).
sider the sharp rotation peak exhibited by all these compounds (except for testosterone (VII)) in the region below 320 mp (Figs. 3 and 4). This sharp peak is similar in position and intensity to that previously' attributed to the isolated 17-keto function but slightly less constant in wave length (range 3 10-320 mp). The hormones concerned (VI, VIIIX I I ) all possess a carbonyl group a t C-20 and this is situated next to an asymmetric center (C-17) just as is the case with the 17-keto group' which is adjacent to the asymmetric carbon C-13. Therefore, we ascribe this rotation peak to the passage of the dispersion curve through the absorption band of an optically active chromophore associated with the 20-keto function. This could be confirmed with pregnan-3P-ol-20-one (XVII) which contains no additional chromophore other than the 20-keto grouping and which exhibited (Fig. 5) a high peak a t 312.5 nip. The peak of androstan-17-one (XVI) also is shown in Fig. 5 in order to permit a comparison between an isolated 20- and 17-keto steroid.
4
t0
a
2 3c 5 V W
XII-+
P
\
ln
2E
-IX
Fig. 4.-Rotatory dispersion curves (295-350 mp) of: ll-dehydrocorticosterone (VIII), cortisone (IX), corticosterorie (X), hydrocortisone (XI), 11 - desoxycorticosterone (XII).
300 350 WAVE LENGTH ( R p )
Fig. 5.-Rotatory dispersion curves (300-350 mp) of: llp-hydroxy-A'androstene - 3,17 - dione (XIII), Reichstein's Substance S (XIV), A4-andro(XV), stene-3,17-dione aridrostan-17-one (XVI), pregnan - 3p - 01 - 20 - one (XVII), etiocholane-3or, 17p-diol-11-one(XVIII).
4362
ELEANOR W. FOLTZ, A. E. LIPPMANAND CARLDJERASSI
As mentioned above, the exact position of this peak in these hormones varies slightly with different substituents in the molecule, but the range of variation (ca. 10 mp) is sufficiently slight so t h a t no correlations could be based on it. On the other hand, the intensity ( i e . , degree of asymmetry) of this peak varies more so-the observed rotation peaks ranging from [ a ]ca. +2500°, for the two ll-ketosteroids VI11 and IX, all the way to +4215' (the highest specific rotation observed so far in the steroid series) for progesterone (VI). I n Fig. 5 a few supplementary compounds (XIII-XVI) have been collected for this region in order to make possible some intensity comparisons. The introduction of an lla-hydroxy group in the l i - k e t o series (XI11 ZIS. XY and XVI) and 20-keto-21-hydroxy series (X ns. XI1 in Fig. 4) results in increased positive rotation, b u t the opposite effect is noted when an additional 1ia-hydroxy substituent is present (hydrocortisone (XI) L I S . Compound S (XIV)).
VOl. 77
the double peaks in the 350-400 mp region occur a t a much more positive rotation in spite of the fact that their peak (at 310-320 mp) due to the 20-keto group is significantly lower than t h a t in other 20ketones (group (b)), can only find an explanation in the assumption that the additional 11-keto substituent is also optically active. If the absorption band responsible for this activity (even though less intense) is situated a t a somewhat longer wave length than t h a t due to the 20-keto group, its effect will be felt more in the 350-400 mp region, causing the double peaks there t o occur higher up on the rotation scale. This was found to be the case. If the positive rotation peak of the 11-keto group is not too strong, it may become obscured by the superimposition of contributions made by the 20-keto group and the A4-3-keto chromophore. The negative peak a t the shorter wave length side of the weaker 11-keto band may coincide with the very strong positive peak of the band corresponding to the 20-keto function, which this would result in deCHzOH crease of intensity of the latter band as observed (see Fig. 4 where the two 11-keto steroids VI11 and IX show the lowest rotation). This explanation could be proved rather conclusively when, subsequent to the first preparation of this manuscript, there became available for measurement a steroid, etiocholane-3a, 1'TP-diol-ll-one (XVIII), the rotatory dispersion curve (Fig. 5 ) of which exhibited all of the features (bathochromic shift coupled with low activity) predicted above for the isolated 11CH3 keto group. These results also are completely i 0 C=O OH compatible with the observationg that the low intensity absorption peak of the 11-keto group occurs a t about 10-13 mp longer wave length than the average steroid ketone. Finally, i t should be mentioned t h a t Brand and co-workersl0 recently have carried out rotatory dispersion measurements of cortisone acetate in chloroform and methanol solution over the range 750-340 r n p without observing any peaks in the ,hi interpretation of the existence of three dispersion curves. Their failure to detect the strikgroups (on the basis of intensity) in the important ing features outlined above resides in the fact that 330-400 mh region now can be presented. Testos- they usually took measurements only in 50-mp interone (VII) (Fig. 2), the single member of group tervals; in the critical range of 350-400 mp, only (a), is also the only hormone which does not have two readings are reported, one a t each of these two any ketonic function in its molecule other than t h a t wave lengths, thus precluding the possibility of dein conjugation with the 4,3-double bond. I t s flat tecting the effect of the A*-3-keto moiety. On the rotation peak a t 290 nip, similar to t h a t found in basis of their results with two steroids, cholesterol L4-cholesten-;3-one,' is ascribed to a separate effect and cortisone acetate, these authors'O state t h a t of the conjugated system, not necessarily' the pas- "the results with steroids indicate t h a t the presence sage of the curve through another optically active of many asymmetric centers is not incompatible absorption band. Since this flat rotation peak is sit- with normal dispersion." This assumption must be uated a t a shorter wave length (290 mp), it makes considered incorrect in the light of our data and its presence less felt in the 330-400 mp region than emphasizes the danger inherent in running measthe sharp peak (312.5 mp) of a 20-ketone (XVII). urements in large intervals. The first of the peaks (at 365 mp) of testosterone (VII) from the long wave length side is negative Mathematical Results (first "minimum") and it is more effective in pulling Just as in the androstane series,' an attempt was the dispersion curve to the negative side than when made by a procedure outlined elsewhere,' to fit oneit is in competition with the large positive rotation term and two-term Drude equations to the present contrihution in the vicinity of the peak (ca. 312.3 series and this proved to be successful in all but nip) due to the 20-keto group. This is illustrated in four cases (V, VI, VII, X). Of these, all except one a striking manner in Fig. 2 by comparison with (9) 0 . Schindler and T. Reichstein, Helr. Chinr. Artii, 37, fi67 progesterone (VI). (1054), a n d references cited therein. The curious behavior of the third group (c), made (10) R. Brand, E. Washburn, B. F. E r h n g e r , E, Ellenbogen, J . up of the two 1I-ketosteroids T'III and IX in which Daniel, F. Lippmann a n d hl. Scheii, THISJ O U R N A L , 76, 5037 (1954).
Aug. 20, 1955
ROTATORY DISPERSION OF STEROID HORMONES
(testosterone (VlI)) had only been measured a t c = 0.1 concentration which, according to our earlier experience,l may cause difficulties in the mathematical treatment. It is noteworthy that in three instances (11, 111, VIII), where satisfactory equations were derived, i t was possible to fit both a one-term and a two-term Drude equation to the same data over much the same range (outside the optically active absorption band). The A0 values calculated from each such pair of equations are in reasonable agreement with each other and with the physical significance attributed to these constants. The calculated ho values for hydrocortisone (XI) (235 mp) and desoxycorticosterone (XII) (258 mp) confirm the tentative conclusion reached earlier that the chromophore a t 240 mp due to the A4-8keto grouping is optically active. The values of Xo for the two 11-keto hormones, ll-dehydrocorticosterone (VIII) (2i3 or 294 mh depending upon the equation) and cortisone (IX) (286 mp), are somewhat high and presumably reflect added rotatory contributions due to other chromophores. The rotatory dispersion results of Brand, et al.,loon cortisone acetate already commented on above were expressed by them in the form of two-term Drude equations, one covering the results in chloroforni and the other in methanol. It appears impossible to determine whether such equations represent the best fit, or, indeed any fit a t all, since only four values were available on which these equations could be tested. Little significance can be attached to these results since two of these values (340 and 350 r n p ) have been shown by us to lie near a region of anomalous dispersion due to passage of the dispersion curve through an optically active band associated with the A4-3-keto group. The close agreement between the calculated Xo values for equilin (I) (282 mp), estrone (11) (291 or 303 mp depending upon equation) and estradiol (IV) (282 mp) with the absorption peak of their phenolic chromophore (ca. 280 mp) leads to the tentative assumption that this particular chromophore is optically active, although in the first two cases the 17-keto chromophore, shown earlier’ to be optically active, undoubtedly plays a part. Experimental Resultss Equilin (I), m.p. 238-240°, furnished by Dr. J . A . Moore, 208’, Parke, Davis and Co. R.D. (Fig. 1): [ a 1 7 0 0 [a1589 256’, [a1306 0+2500°, “rnax.” [a]317.6 $3778’; c = 0.10; temp. 24-26 . Drude equation: [MI = 160/(A2 - 0.0789) 69.3/A2; A0 282 mp; % deviation [MIobs,, [Mlcalcd: *1.4%, 620-350 nip; *3.4%, 650-350 mp. Estrone (11), m.p. 260-261’; Amax 289, 281-282 m p , log E 3.38, 3.42, shoulder 315 m p , log 1.68; from Syntex, S.A. R . D . (Flg. 1): [ a 1 7 0 0 t 1 0 9 ” , [0r]5s9 +160”, [ ( Y ] 3 i o +1715’, “max.” [ a 1 3 2 0 $3064 ; c = 0.10; temp. 23-25’; Drude equation: one-term, [MI = 113/(A2 - 0.0846); Ao 291 mp; % deviation [Mlobsd - [hIjcaled: 1 0 . 8 % , 650-370 m p ; *2.1%, 700-360 m p . Two-term, [MI , = 89.5/(A2 - 0.0920) 28.8/h2; ha 303 m p ; yo deviation [Mlobsd - [MIcaicd: *1.2%, 650-350 mp; *3.2%, 700325 m p . Equilenin (111), y . p . 252-254”. R.D. (Fig. 1): [ a 1 7 0 0 4-68”, [ ~ ] S S S 100 , [ L Y ] ~ ~+672’; o c = 0.10; temp. 2324”. Drude equation: [MI = 65.7/(X2 - 0.0956); XO 309 mp; %deviation [MIobsd [M]oslod: +1.4%, 700-365 mp. Two-term, [ A I ] = 62.8/(A* 0.0970) 3.73/A2; ho 311 lnp; % deviation [MIobsd - [M]caled: &l.o%, 700-370 mp; *1.4%, 700-370 m p ; f 2 . 2 % , 700-365mp. Estradiol (IV), m.p. 178-179”, from Syntex, S.A. R.D. (Fig. 1): [a1700+72”, [ N ] : S Q +98”, [ a 1 3 1 5 +441°; G = 0.10;
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temp. 24-25’. Drude equation: [MI = 9.52/(X2 - 0.0798) f 7.96/h2; Xo 282 mp; % deviation [Mjobad [M]caicd: 1 2 . 9 % , 650-330 mp. 6-Dehydroestradiol (V), m.p. 229.5-230.5’. R.D. (Fig. 1): [01]700 -1,32”, [ a 1 5 8 9 -186p, [cY]336 -1602’; c = 0.10; temp. 24-26 . Drude equation: [MI = -141/(X2 0.0800); AO 283 m p ; % deviation [M]obsrl [M]osled: 3 ~ 1 . 7 % ; 520-335 mp. Progesterone (VI), m.p. 128-129’; A,,,,, 292-294, 330332 m p , log c 1.75, 1.68, shoulders 301-305, 313-317 mp, log e 1.74, 1.71, inflection 343 m p , log E 1.57; furnished by Syntex, S.A. R.D. (Fig. 2): [ a j 7 0 0 +$20’, [ C Y ] S+183”, ~ [a]300 +2977’,,, “rnax.” [ a 1 3 8 6 +568 , “min.” [ 0 1 ] 3 6 7 ~ 6 +418O, “rnax. [a]3i7.~ 578’, “rnin.” [a]352.5 513 , “max.” CY]^^^ +4215 ; c = 0.10; temp. 24-25”. Testosterone (VII), m.p. 153.5-154.5’; ,,A 330-331 m p , log e 1.66, shoulder 322-325 m p , log e 1.64; inflections 362, 355. 346. 340 mu. loe c 1.10. 1.23. 1.51. 1.56: fromSvn-
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c = 0.10; temp. 24-25‘. R.D.: [ a ] 7 0 ~+69.0’, [a]689 +100.8’, [a1375 +35.0°, “max.” [ a 1 4 2 0 +192.3’; c = 1.00. 11-Dehydrocorticosterone (VIII), m.p. 175-180’; shoulder 311-313 m p , log e 2.08; inflections 290, 302, 335, 344, 352 mp, log e 2.20, 2.15, 1.87, 1.73, 1.65; furnished by Dr. K. Pfister, Merck and Co., Inc. R.D. (Figs. 3 and 4): [a1700 [ ~ ~ S S +235”, Q [a1300+ ! % 5 ” , “rnax.” [ 0 1 ] 3 7 7 ~ ~ +987”, min.” [a1370 954”, “max. [ a ] 3 5 7 . 5 - 360 +lo58 , ‘min.” [a]35; 1042 , “rnax.” [ a ] 3 1+2488O; 6 c = 0.10; temp. 23-25 . Drude equation: one-term, [MI = 222/ (A2 0.0747); Xo 273 nip; % deviation [M]obs,i- [MIcaled: 1 0 . 8 % , 650-400 mp; f1.7%, 650-390 nip. Two-term, [MI = 169/(A2 - 0.0864) 58.8/A2; A0294mp; yodeviation *1.2%,650-380mp; 3Z1.9%, 700-380 m p . Cortisone (IX), m.p. 215-217’; A,,, 284-285 m p , log e 2.15, shoulder 332 nip, log e 1.65; inflections 318, 340, 348, 360 nip, log e 1.82, 1.56, 1.t7, 1.15; Syntex, S . A . R.D. (Figs. 3 and 4): [ ~ I ~ o$122 o , [ a 1 5 8 9 +196’, [a];06 4-891’. “max.” la17-~4-933’. “miii.” +SO9
+!%p,
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+887.1”; c = 1.00; temp. 24-25.”. Drude equation: [MI = 188/(A2 - 0.0816), from c = 1.00 data; ho 286 m p ; % deviation [MIobad- [M]oa~cd: *0.7%, 700-425 mp. Corticosterone (X), m.p. 181-185’; slight Amax 319, 329 m p , log e 1.93, 1.92, shoulders 290, 340-342 m p , log e 2.14, 179, inflection 358 mp, log e 1.43; supplied by Dr. K. Pfister, Merck and Co., Inc. R.D. (Figs. 3 and 4): [ L Y ] , ~ ~ +134”, [ a ] j g g +194’, [ a ] s s j +1989”, “rnax.” +551”, 398’, “rnax.” [ a ] 3 5 7 . 6 534’, “min.” “min.” [a]367.5 [ a ] 3 5 ~ . % +512’, “max.” [ a ] 3 0 ~ - 3 1 0 $4022’; c = 0.10; temp. 23-20 . Hydrocortisone (XI), m . p . 215-218’; A,,,,, 290 m p , log e 2.01; inflections 315, 324, 332, 338, 346, 357 mp, log e 1.82, 1.75, 1.73, 1.65, 1.56, 1.23; furnished by Dr. E(. Pfister, Merck and Co., Inc. R.D. (Figs. 3 and 4): [ a ] 7 o o +113’, [ a 1 6 8 9 162”, [a1300+1202O, “max.” CY]^^^ i-456:: “rnin. ” [ a ]387.5 t 312 ’, “max .” [ a ]337.5 +460’, ‘‘rnin. [ a ] 3 6 2 . ; +428O, “niax.” [ a 1 3 1 6 -/-3506”; c = 0.10; temp. 23-25 . Drude equation: [MI = 172/(A2 - 0.0551); AO 235 mp; %deviation [Mlohsd [M]calcd: i l . O % , 620410 m p ; &3.7%, 700-400 mp. Desoxycorticosterone (XII), m.p. 139-140’; shoulders 285-289, 333, 347 mp, log e 2.04, 1.71, 1.56; inflections 321, 357, 365 inp, log c 1.74, 1.28, 1.07; from Syntex, S.A. R.D. (Figs. 3 and 4): [a1700+94’, [ a 1 5 8 9 +149”, [a];00 +1731’, “max.” [ C Y ] ~ Y S ,;t+48:,, “min.” [ a l 3 s L . 5 $325 , “max.” [a1360 428’, min. [a]351.5 +394 , max.” [a]310 +2952”; c = 0.10; temp. 24.5-26.5”. R.D.: [ a ] 7 0 0 +110.6”, [ 0 r ] ~ 7 5 +437.3”, “niax.” +176.1”. L = 1.00; temp. 24-25’. Drude equation: [MI = 154) (A2 0.0667), from c = 1.00 data; XO 258 m p ; % deviation w]obsd [ M ] c a l e d : +0.5%, 700-475 m p ; &1.2%, 700450 inp. Ad-Androstene,-; lp-of;3,17-dione (XIII), m.p. 194-199’. R.D. (Fig. 5 ) : max. [alal;5 +3945’; c = 0.10; temp. 24-25’.’‘ 17~-Hydroxydesoxycorticosterone(XIV), 1n.p. 205-210’; ,,,A 286-289 mp, log E 2.03, shoulders 349, 330 m p , log c
+
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(11) Data based on one determination
A. E. LIPPMAN, ELEANOR N7.FOLTZ A N D CARLDJERASSI
4364
1.47, 1.70; inflections 364, 358, 340, 315 mp, log e 0.97; 1.17,1.60,1.18; fromSyntex, S.A. R.D. (Fig. 5): “max. [ e ] i5 ~ 3786’; c = 0.10; temp. 23-24’.” Pregnane-3P-ol-20-one(XVII),m.p. 144-146’; L.x 238291 mp, log E 1.53; supplied by Syntex, R.D. (Fig. 5 ) : [ ~ I ~ o o 5 5 ” , [ a ] m +So,[ 0 1 ] 2 9 5 4-601 , “max.” [01]312.1 2393’; c = 0.10; temp. 2 5 O . 1 1 Etiocholane-3~~,l7p-diol-ll-one (XVIII),1i1.p. 261-262”;
+
+
S.3.
+
[ COSTRIBUTION FROM
THE
Vol. ’77
Amax 302-303 mfi, log E 1.51, shoulders 311-313, 292-294 mp, log e 1.46, 1.46; inflections 320, 325 mp, log e 1.28,
1.16; supplied by Dr. E. B. Hershberg and Dr. H. L. Herzog, Schering Corp. R.D. (Fig. 5 ) : [ a ] y o +39”, [ 0 1 1 5 ~ 9 + j g o , [a]30o + 5 3 O , ‘(Inax.’’ [ a ] 3 2 7+679 5 ; c = 0.10; temp. 240.11
DETROIT,MICHICAU
DEPARTMENT O F CHEMISTRY O F WAYNE UNIVERSITY]
Optical Rotatory Dispersion Studies. 111.’ The Cholestane Series2 BY
E. LIPPBIAN, ELEANOR W. FOLTZ .4ND CARLDJERASSI RECEIVED MARCH 16, 1955
The rotatory dispersion curves of various isomeric cholestenols and ketones of the cholestanc series are reported anti disSome of the mathematical implications are also presented.
cussed.
Cholesterol (V) is one of the very few steroids, the rotatory dispersion of which has been examined prior to our own investigation^'^^ in this field and initial measurements with this substance in the visible region have been carried out as early as 1863.4a \Ve now have measured the rotatory dispersion of various members of the cholestane series and in particular of various double bond isomers of cholesterol. These substances, lacking strong chromophores such a s carbonyl groups, should show “normal” dispersion curves and hence should be more amenable to mathematical treatment. IVe also l i a i ~included several ketones of the cholestane series in order to complement the earlier ~ t u d i e s of ‘~~ the rotatory dispersion of carbonyl-containing steroids. The dispersion curves of the ketones studied in this series are shown in Fig. 2 and the results fully confirm the earlier conclusion^.^^^ Cholestan-3one (1x1 is very similar to androstan&one, discussed p r e v i ~ u s l yin , ~ that i t shows the positive rotation peak a t 3 15m p ascribed to a weakly asymrnetric chromophore associated with the carbonyl function at C - 3 ; furthermore, this substance shows the 0 negligible effect t h a t the cholestane side chain apVI11 I S s SI pears t o have on the rotation of the molecule. Considering the region :i50-400 mp, so important oids in our series1m3which do not have an additional for unsaturated ketones, A4-cholesten-:3-one (VII) saturated carbonyl group elsewhere in the moleexhibits a “ m a ~ i r n u r n ”a ~t 360 m p and “minima” a t cule. Another typical property of these two unsatand X O nip, corresponding to an optically ac- urated ketones is t h a t the “minimum” a t 36,5 nip octjvc :ibsorptiori band a t :353 111p (mean of positive curs a t a more positive rotation than the “mini1)caL a t :;(jO nip and iiegative peak a t 350 nip). mum” a t 350 inM and both these features can be \\%le the position of this band (and the peaks defin- considered as the true characteristics of the A4-3ing i t ) is in accord with that of other A4-?,-keto ster- keto dispersion curve. In all the other A4-,‘3-ltetooids,’,3it is noteworthy that these two peaks occur steroid^,',^ this order is reversed and this clearly is a t :I negative rotation. The only other A4-;3-ke- due to the fact that in those instances the A4-:3-keto toiic exhibiting such a behavior is testosterone‘ and band is coming under the influence of the very much these two compounds are the only A4-:3-ketoster- stronger and highly positive band (in the 820 mp ’ I , Paper 11, E. IV. F o l t z , A . E . 1,ippman and C. Djerassi, THIS region) corresponding to the additional saturated carbonyl group (at C-11, 17 or 20) which tends to J U I . X & A L . 7 7 , 4339 ( 1 9 5 5 ) . ( 2 ) Supported by a grant from t h e National Science Foundation. “pull up” this part of the curve to more positive (3) C. Djerasii, E. W. Foltz a n d A . E. Lippman, THISJ O U R X A L , 7 7 , rotation values. It should be emphasized, how4354 (103.5). ever, that this does not interfere with the recogni( t ) (a) 0 . Lindennlayer, J . p i o k l . Chem., [ l ]90, 323 (1863); (b) L . tion of the A4-3-keto moiety through its rotatory T x h u g a e f f , %. p h y s i k . Chem., 7 6 , 469 (1911). ( c ) Cholesterol has l , r v t t me:i?:ird uver t h e range ?RO-750 mp by E. Brand, E . Washdispersion band, but rather offers :i further refineI: I, l~ildil&!?r, 1.;. F;lleuiiuyen, I . Daniel, I;. I . i p p m a n n d n d 31. ment of this niethod through a coilsideration of both I> J , I I X Y . \ I . , 7 6 , .XJ3i I position and reltrtive iniensity of ‘.iii:ixi:u:L” a i i t i ri.1 ‘I ir,r u
